Process for producing indolocarbazole derivatives

ABSTRACT

In the formulae, R 1 , R 2 , and R 3  independently represent lower alkyl or aryl, and R 4  represents lower alkyl. 
     The present invention relates to a process for producing an indolocarbazole derivative represented by Formula (II), comprising the acidic treatment of a silylated indolocarbazole derivative represented by Formula (VI).

TECHNICAL FIELD

The present invention relates to an industrial process for selectivelyand efficiently producing indolocarbazole derivatives which have proteinkinase C-inhibiting activity.

BACKGROUND ART ##STR2## In the formulae, R⁴ represents lower alkyl.

Hereinafter, compounds represented by Formula (I), Formula (II), Formula(III), and Formula (IV) are referred to as Compound (I), Compound (II),Compound (III), and Compound (IV), respectively. The same applies to thecompounds of other formula numbers.

It is known that Compound (II) has protein kinase C-inhibiting activity,and the process for producing Compound (II) as shown above is disclosedin Japanese Published Unexamined Patent Application No. 155284/87.According to the process, Compound (II) is directly produced fromCompound (I). However, in the process, Compound (III) wherein a nitrogenatom in the amide group is lower-alkylated, and Compound (IV) whereinboth of a hydroxyl group and a nitrogen atom in the amide group arelower-alkylated are produced in large quantities as by-products at thesame time. Thus, the yield of the desired Compound (II) is low, and acomplicated technique unsuitable for mass production, such as silica gelchromatography, is required for purification.

DISCLOSURE OF THE INVENTION

The present invention relates to a process for producing anindolocarbazole derivative represented by Formula (II), comprising:selective silylation of a nitrogen atom in the amide group of Compound(I) for obtaining a compound represented by Formula (V): ##STR3##wherein R¹, R², and R³ independently represent lower alkyl or aryl;lower-alkylation of Compound (V) to obtain a silylated indolocarbazolederivative represented by Formula (VI): ##STR4## wherein R¹, R², R³, andR⁴ have the same meanings as defined above; and the acidic treatment ofthe silylated indolocarbazole derivative.

In addition, the present invention provides a silylated indolocarbazolederivative represented by Formula (VI).

In the definitions of the groups in Formula (I) to Formula (VI), thelower alkyl means a straight-chain or branched alkyl group having 1 to 6carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl pentyl, isopentyl, neopentyl, and hexyl. The aryl means agroup such as phenyl and naphtyl.

The process of the present invention is described in detail below.##STR5## In the formulae, X represents halogen, and R¹, R², R³, and R⁴have the same meanings as defined above.

The halogen means chlorine, bromine, or iodine.

The starting Compound (I) can be obtained according to the methoddescribed in Japanese Published Unexamined Patent Application No.41489/85.

Step 1

Compound (V) can be obtained by reacting Compound (I) with 1 to 20equivalents of tri-substituted silyl chloride in the presence of 1 to 20equivalents of a base such as triethylamine, pyridine and imidazole, ina solvent at -30° to 50° C. for 0.5 to 24 hours. As a solvent, ahalogenated hydrocarbon such as methylene chloride, chloroform, ethylenedichloride and carbon tetrachloride, an ester such as ethyl acetate,isopropyl acetate, tert-butyl acetate, isobutyl acetate and butylacetate, and dimethylformamide are used singly or in combination in anamount of 1 to 50-fold (by weight) based on Compound (I).

Step 2

Compound (VI) can be obtained by reacting Compound (V) with 1 to 20equivalents of alkyl halide in the presence of 1 to 20 equivalents of abase such as lithium hydroxide, potassium hydroxide, sodium hydroxideand sodium hydride, in a solvent at -30° to 50° C. for 0.5 to 24 hours.As a solvent, dimethylformamide and dimethylsulfoxide are used singly orin combination in an amount of 1 to 50-fold (by weight) based onCompound (V).

Step 3

Compound (II) can be obtained by treating Compound (VI) with 1 to 100equivalents of hydrochloric acid, sulfuric acid, acetic acid,hydrobromic acid, trifluoroacetic acid, methane sulfonic acid, or thelike, in a solvent or without a solvent. As a solvent, an alcohol suchas methanol, ethanol and isopropanol, acetone, and acetonitrile are usedsingly or in combination in an amount of 1 to 100-fold (by weight) basedon Compound (VI). The reaction is carried out at -30° C. to the boilingtemperature of the employed solvent for 0.5 to 24 hours.

The intermediates and the desired compounds in the process describedabove can be easily isolated and purified by subjecting them to apost-treatment conventionally used in organic synthetic chemistry suchas extraction, washing, drying and concentration, followed bycrystallization and filtration. The intermediates may also be subjectedto the subsequent reaction without purification, after the reaction orafter the post-treatment.

Compound (II) obtained as described above has protein kinaseC-inhibiting activity (Japanese Published Unexamined Patent ApplicationNo. 155284/87).

Examples and Comparative Example are described below.

The physicochemical data of each compound were determined by thefollowing apparatus.

Melting point: Mettler FR61

MS: Hitachi M-80B (determined by SIMS method)

¹ H-NMR: Nippon Bruker AC-300 (300 MHz)

IR: Shimadzu FTIR-4300 (determined by KBr method)

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1

Methyl 9α, 10β, 12α-2-(tert-butyldimethylsilyl)-2, 3, 9, 10, 11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo-[3,4-i][1,6]benzodiazocine-10-carboxylate [Compound (V-1)] ##STR6##

Ethyl acetate (800 ml), dimethylformamide (50 ml) , and triethylamine(45.0 ml, 321 mmol) were added to methyl 9α, 10β,12α-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylate[Compound (I)] (50.0 g, 107 mmol), and a solution oftert-butyldimethylsilylchloride (48.3 g, 321 mmol) dissolved in ethylacetate (200 ml) was added thereto at room temperature, followed bystirring for 5 hours while maintaining the temperature in a range of 25°to 35° C. After partition of the reaction mixture by adding 1000 ml ofwater, the organic layer was washed twice with 1000 ml of a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The desiccating agent was filtered off, the solvent wasdistilled off under reduced pressure, and 600 ml of methanol was addedto the residue, followed by stirring for 30 minutes at room temperature.After adding 150 ml of water, the mixture was stirred again for 30minutes. Stirring was further continued for 5 hours under ice-cooling.The precipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 51.7 g (89.0mmol, yield 83.2%) of the title compound.

Melting Point: 235°-241° C. (decomposition)

MS (m/z): 582 (M⁺ +1)

¹ H-NMR(300 MHz,DMSO-d₆) δ(ppm): 9.25(1H, d,J=8.0 Hz), 8.17 (1H,d,J=7.7Hz), 7.99(1H, d,J=8.5 Hz), 7.95(1H, d, J=8.3 Hz), 7.54(2H,t,J=7.3 Hz),7.42(1H, t,J=7.3 Hz), 7.34(1H, t,J=7.6 Hz), 7.20(1H,t,J=5.1 Hz),6.44(1H, s), 5.15(2H, d,j=4.7 Hz), 3.97(3H,s), 3.21(1H, d, J=5.0 Hz),2.20(3H,s), 2.05(1H, dd, J=13.8,4.5 Hz), 1.08(9H,s), 0.58(6H,s)

IR (KBr) v (cm⁻¹): 1746, 1670, 1585, 1458, 1347, 1275, 1202

EXAMPLE 2

Methyl 9α, 10β,12α-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-2-triethylsilyl-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (V-2)] ##STR7##

Ethyl acetate (10 ml), dimethylformamide (0.5 ml), and triethylamine(0.45 ml, 3.21 mmol) were added to Compound (I) (500 mg, 1.07 mmol), andtriethylsilylchloride (0.54 ml, 3.22 mmol) was added thereto at roomtemperature, followed by stirring for 5 hours and 20 minutes whilemaintaining the temperature in a range of 25° to 35° C. After partitionof the reaction mixture by adding 10 ml of water, the organic layer waswashed twice with 10 ml of a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate. The desiccatingagent was filtered off, the solvent was distilled off under reducedpressure, and the residue was subjected to column chromatography on 10 gof silica gel (chloroform:ethyl acetate=5:1). After evaporation of thesolvent under reduced pressure, 10 ml of hexane was added to theresidue, followed by stirring for 5 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 437 mg (0.752mmol, yield 70%) of the title compound.

Melting Point: 155°-158° C. (decomposition)

MS (m/z): 582 (M⁺ +1)

¹ H-NMR(300MHz,CDCl₃) δ(ppm): 9.39(1H,d,J=8.0 Hz), 7.96 (1H,d,J=7.5 Hz),7.78(1H,d,J=8.4 Hz), 7.49(2H, d, J=3.5 Hz), 7.45(1H, dd, J=8.3,1.1 Hz),7.37(1H, t, J=7.5 Hz), 7.34(1H, dt,J=8.1,4.0 Hz), 6.92(1H, dd, J=7.3,4.9Hz), 5.02(2H,s), 4.09(3H,s), 3.67(1H,s), 3.25(1H, dd, J=14.3,7.4 Hz),2.25(1H,dd, J=14.3, 4.9 Hz), 2.23(3H,s), 1.2-1.0(15H,m)

IR(KBr) v(cm⁻¹): 1732, 1668, 1587, 1456, 1132, 743

EXAMPLE 3

Methyl9α,10β,12α-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-2-triphenylsilyl-9,12-epoxy-1H-diindolo-[1,2,3,-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (V-3)] ##STR8##

Ethyl acetate (8.0 ml) , dimethylformamide (0.5 ml), and triethylamine(0.45 ml, 3.21 mmol) were added to Compound (I) (500 mg, 1.07 mmol) ,and a solution of triphenylsilylchloride (947 mg, 3.21 mmol) dissolvedin ethyl acetate (2.0 ml ) was added thereto at room temperature,followed by stirring for 5 hours while maintaining the temperature in arange of 25° to 35° C. After partition of the reaction mixture by adding10 ml of water, the organic layer was washed twice with 10 ml of asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. The desiccating agent was filtered off, the solventwas distilled off under reduced pressure, and 6.0 ml of methanol wasadded to the residue, followed by stirring for 30 minutes at roomtemperature. Stirring was further continued for 5 hours underice-cooling. The precipitated solid was collected by filtration and thesolvent was distilled off by drying under reduced pressure to give 689mg (0.949 mmol, yield 88.7%) of the title compound.

Melting Point: 218°-222° C. (decomposition)

MS (m/z): 726(M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.37(1H, d,J=8.0 Hz), 7.9-7.7 (6H,m),7.74 (1H, d,J=7.7 Hz), 7.56(1H, d,J=7.7 Hz), 7.5-7.3(12H,m),7.3-7.2(2H,m), 6.90(1H, dd, J=7.2, 4.9 Hz), 4.90 (2H,s), 4.07 (3H,s),3.69 (1H,s), 3.24 (1H,dd,J=14.3,7.4 Hz), 2.24 (1H,dd, J=14.3,4.9 Hz),2.20 (3H,s)

IR (KBr) v (cm⁻¹): 1732, 1668, 1587, 1456, 1132, 743

EXAMPLE 4

Methyl 9α, 10β,12α-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-2-triisopropylsilyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (V-4)] ##STR9##

Ethyl acetate (10 ml), dimethylformamide (1.4 ml), and triethylamine(0.9 ml, 6.44 mmol) were added to Compound (I) (500 mg, 1.07 mmol) , andtriisopropylsilylchloride (1.38 ml, 6.45 mmol) was added thereto at roomtemperature, followed by stirring for 24 hours while maintaining thetemperature in a range of 25° to 35° C. After partition of the reactionmixture by adding 10 ml of water, the organic layer was washed twicewith 10 ml of a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. The desiccating agent was filtered off,the solvent was distilled off under reduced pressure, and the residuewas subjected to column chromatography on 20 g of silica gel(hexane:ethyl acetate=2:1). After evaporation of the solvent underreduced pressure, 18 ml of hexane was added to the residue, and themixture was stirred for 30 minutes at room temperature and furtherstirred for 5 hours under ice-cooling. The precipitated solid wascollected by filtration and the solvent was distilled off by dryingunder reduced pressure to give 572 mg (0.917 mmol, yield 85.7%) of thetitle compound.

Melting Point: 230°-234° C. (decomposition)

MS (m/z): 624 (M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.41 (1H,d,J=8.0 Hz), 7.96 (1H,d,J=6.8Hz), 7.78 (1H, d,J=8.3 Hz), 7.49 (2H, d, J=3.7 Hz), 7.45(1H, dd,J=8.3,1.1 Hz), 7.38(1H, t, J=7.1 Hz), 7.34(1H,dt,J=8.0,4.0 Hz), 6.92(1H,dd, J=7.3,4.6 Hz), 5.12(2H,s), 3.97(3H,s), 3.25(1H, dd, J=14.6,7.3 Hz),2.25(1H, dd, J=14.3,4.9 Hz), 2.22 (3H,s), 1.79(3H,dt,J=15.2,7.6 Hz),1.27(18H, d, J=7.5 Hz)

IR (KBr) v(cm⁻¹): 1747, 1670, 1587, 1458, 1365, 1276, 1200, 744

EXAMPLE 5

Methyl9α,10β,12α-2-(tert-butyldiphenylsilyl)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo-[3,4-i][1,6]benzodiazocine-10-carboxylate [Compound (V-5)] ##STR10##

Ethyl acetate (10 ml), dimethylformamide (0.5 ml), and triethylamine(1.35 ml, 9.69 mmol) were added to Compound (I) (500 mg, 1.07 mmol), andtert-butyldiphenylsilylchloride (2.52 ml, 9.69 mmol) was added theretoat room temperature, followed by stirring for 24 hours while maintainingthe temperature at 50° C. After partition of the reaction mixture byadding 10 ml of water, the organic layer was washed twice with 10 ml ofa saturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. The desiccating agent was filtered off, the solvent wasdistilled off under reduced pressure, and the residue was subjected tocolumn chromatography on 80 g of silica gel (hexane:ethyl acetate=2:1).After evaporation of the solvent at reduced pressure, 10 ml of hexanewas added to the residue, and the mixture was stirred for 30 minutes atroom temperature and further stirred for 5 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 572 mg (0.587mmol, yield 54.9%) of the title compound.

Melting Point: 186°-198° C. (decomposition)

MS (m/z): 706 (M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.44 (1H,d,J=8.0 Hz), 7.8-7.7(4H,m),7.5-7.3 (11H,m), 7.21 (1H, t,J=7.4 Hz), 6.92(1H, dd, J=7.2,5.2 Hz),4.76(2H,s), 4.09(3H,s), 3.66(1H,s), 3.25(1H,dd, J=14.3,7.4 Hz), 2.25(1H,dd, J=14.3, 4.9 Hz), 2.20 (3H,s), 1.42 (9H,s)

IR (KBr) v(cm⁻¹): 1733, 1676, 1587, 1458, 1111, 741

EXAMPLE 6

Methyl 9α,10β,12α-2-(tert-butyldimethylsilyl)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo-[3,4-i][1,6]benzodiazocine-10-carboxylate[Compound (VI-1)] ##STR11##

Under nitrogen atmosphere, 1000 ml of dimethylformamide and 16.5 ml (258mmol) of methyl iodide were added to 50.0 g (86.1 mmol) of Compound(V-1) obtained in Example 1, and 2.05 g (86.1 mmol) of lithium hydroxidewas added thereto at room temperature, followed by stirring for one hourwhile maintaining the temperature in a range of 20° to 30° C. Then, 2.05g (86.1 mmol) of lithium hydroxide was added to the mixture and themixture was stirred for one hour while maintaining the temperature in arange of 20° to 30° C. Further, 2.05 g (86.1 mmol) of lithium hydroxidewas added to the mixture and the mixture was stirred for 3 hours whilemaintaining the temperature in a range of 20° to 30° C. For partition,the reaction mixture was added to a cooled mixture of 1250 ml of ethylacetate, 1000 ml of water, 25.0 g of citric acid, and 50.0 g of sodiumchloride. After extraction of the aqueous layer with 500 ml of ethylacetate, the organic layer was combined, washed once with 500 ml ofwater and twice with 500 ml of a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The desiccating agentwas filtered off, the solvent was distilled off under reduced pressure,and 1000 ml of acetonitrile was added to the residue, followed bystirring for 30 minutes at room temperature. After ice-cooling, 100 mlof water was added thereto, and the mixture was further stirred for 3hours under ice-cooling. The precipitated solid was collected byfiltration and the solvent was distilled off by drying under reducedpressure to give 46.4 g (78.0 mmol, yield 90.6%) of the title compound.

Melting Point: 260°-272° C. (decomposition)

MS (m/z): 596(M⁺ +1)

¹ H-NMR(300 MHz,DMSO-d₆) δ(ppm):9.23(1H, d,J=8.1 Hz), 8.13 (1H, d,J=7.7Hz), 7.98(1H, d,J=8.2 Hz), 7.89(1H, d, J=8.5 Hz), 7.53(2H,t,J=7.6 Hz),7.40(1H, t,J=7.5 Hz), 7.33(1H,t,J=7.5 Hz), 7.28(1H,t,J=7.5 Hz), 5.14(2H,s), 4.01(3H,s), 3.54(1H, dd, J=13.7,7.5 Hz), 3.05(3H, s), 2.21(3H,s),2.10(1H, dd, J=13.9,4.9 Hz), 1.07(9H, s), 0.56(6H,s)

IR(KBr) v(cm⁻¹): 1732, 1664, 1589, 1456, 1350, 1272, 1098

EXAMPLE 7

Methyl9α,10β,12α-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-2-triethylsilyl-9,12-epoxy1H--diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (VI-2)] ##STR12##

Under nitrogen atmosphere, 3.0 ml of dimethylformamide and 80 μl (1.29mmol) of methyl iodide were added to 150 mg (0.258 mmol) of Compound(V-2) obtained in Example 2, and 31 mg (1.29 mmol) of lithium hydroxidewas added thereto under ice-cooling, followed by stirring for 3.5 hourswhile maintaining the temperature below 5° C. The reaction mixture wasadded to 5.0 ml of ethyl acetate. After partition, the aqueous layer wasextracted with 10 ml of ethyl acetate, and the organic layer wascombined, washed once with 10 ml of water and twice with 10 ml of asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. The desiccating agent was filtered off, the solvent wasdistilled off under reduced pressure, and the residue was purified bycolumn chromatography on 10 g of silica gel (hexane:ethyl acetate=3:1).The solvent was distilled off by drying under reduced pressure to give23 mg (0.039 mmol, yield 15.0%) of the title compound.

Melting Point: 225°-228° C. (decomposition)

MS (m/z): 596 (M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.38(1H, d,J=8.0 Hz), 7.94 (1H,d,J=7.2Hz), 7.89(1H,d,J=8.4 Hz), 7.6-7.4(3H,m), 7.4-7.3(2H,m), 6.99(1H,dd,J=7.2,5.2 Hz), 5.02(2H, s), 4.04(3H,s), 3.36(1H, dd, J=13.7,7.3 Hz),3.12(3H, s), 2.22(3H,s), 2.21(1H, dd, J=13.2,5.3 Hz), 1.2-1.0 (15H,m)

IR(KBr) v(cm⁻¹): 1740, 1662, 1587, 1454, 1367, 1265, 1201, 1148, 1096,741

EXAMPLE 8

Methyl 9α,10β,12α-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-2-triphenylsilyl-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (VI-3)] ##STR13##

Under nitrogen atmosphere, 6.0 ml of dimethylformamide and 0.13 ml (2.07mmol) of methyl iodide were added to 300 mg (0.413 mmol) of Compound(V-3) obtained in Example 3, and 49 mg (2.07 mmol) of lithium hydroxidewas added thereto at room temperature, followed by stirring for 50minutes while maintaining the temperature in a range of 20° to 30° C.For partition, the reaction mixture was added to a cooled mixture of 7.5ml of ethyl acetate, 6.0 ml of water, 163 mg of citric acid, and 240 mgof sodium chloride. After extraction of the aqueous layer with 5.0 ml ofethyl acetate, the organic layer was combined, washed once with 5.0 mlof water and twice with 5.0 ml of a saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. The desiccatingagent was filtered off, the solvent was distilled off under reducedpressure, and the residue was purified by column chromatography on 15 gof silica gel (hexane:ethyl acetate=2:1). The solvent was distilled offby drying under reduced pressure to give 23 mg (0.032 mmol, yield 7.7%)of the title compound.

Melting Point: 222°-230 ° C. (decomposition)

MS (m/z): 740 (M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.35(1H, d,J=8.0 Hz), 7.9-7.7(7H,m),7.7-7.3(13H,m), 7.3-7.2(2H,m), 6.99(1H, dd, J=7.2, 5.2 Hz), 4.90 (2H,s),4.03(3H,s), 3.37(1H, dd, J=13.3,7.3 Hz), 3.12(3H,s), 2.21(1H, dd,J=11.5, 7.0 Hz), 2.21 (3H,s)

IR(KBr) v(cm⁻¹): 1728, 1674, 1589, 1458, 1365, 1272, 1205, 1134, 1096,746

EXAMPLE 9

Methyl9α,10β,12α-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-2-triisopropylsilyl-9,12-epoxy-1H-diindolo[1,2,3,-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylate[Compound (VI-4)] ##STR14##

Under nitrogen atmosphere, 3.0 ml of dimethylformamide and 90 μl (1.44mmol) of methyl iodide were added to 150 mg (0.240 mmol) of Compound(V-4) obtained in Example 4, and 28 mg (1.16 mmol) of lithium hydroxidewas added thereto under ice-cooling, followed by stirring for 4.5 hourswhile maintaining the temperature in a range of 0° to 5° C. Forpartition, the reaction mixture was added to a cooled mixture of 10 mlof ethyl acetate and a 0.5mM phosphate buffer (pH 5.9). After extractionof the aqueous layer with 10 ml of ethyl acetate, the organic layer wascombined, washed once with 4.0 ml of water and three times with 4.0 mlof a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The desiccating agent was filtered off, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on 10 g of silica gel (hexane:ethylacetate=3:1). The solvent was distilled off by drying under reducedpressure to give 99 mg (0.155 mmol, yield 64.7%) of the title compound.

Melting Point: 272°-275° C. (decomposition)

MS (m/z): 638 (M⁺ +1)

¹ H-NMR (300 MHz, CDCl₃) δ(ppm): 9.40(1H, d,J=7.9 Hz), 7.94 (1H, d,J=7.4 Hz) , 7.89(1H, d,J=8.4 Hz), 7.6-7.4(3H,m), 7.4-7.3(2H,m) ,6.98(1H, dd, J=7.2,5.2 Hz), 5.12(2H, s) , 4.11 (3H,s), 3.36(1H, dd,J=13.2,7.3Hz), 3.12(3H, s), 2.22(3H,s), 2.21(1H, dd, J=13.2,5.3 Hz),1.79 (3H, dt, J=15.2,7.6 Hz) , 1.27 (18H,d,J=7.5 Hz)

IR (KBr) v(cm⁻¹): 1740, 1662, 1587, 1454, 1367, 1265, 1201, 1148, 1096,741

EXAMPLE 10

Methyl9α,10β,12α-2-(tert-butyldiphenylsilyl)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo-[3,4-i][1,6]benzodiazocine-10-carboxylate [Compound (VI-5)] ##STR15##

Under nitrogen atmosphere, 3.0 ml of dimethylformamide and 66 μl (1.06mmol) of methyl iodide were added to 150 mg (0.213 mmol) of Compound(V-5) obtained in Example 5, and 26 mg (1.09 mmol) of lithium hydroxidewas added thereto at room temperature, followed by stirring for 3 hourswhile maintaining the temperature in a range of 20° to 30° C. Forpartition, the reaction mixture was added to a cooled mixture of 5 ml ofethyl acetate and 5 ml of a 0.5 mM phosphate buffer (pH 5.9). Afterextraction of the aqueous layer with 10 ml of ethyl acetate, the organiclayer was combined, washed once with 10 ml of water and three times with10 ml of a saturated aqueous solution of sodium chloride, and dried overanhydrous magnesium sulfate. The desiccating agent was filtered off, thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on 10 g of silica gel (hexane:ethylacetate=3:1). The solvent was distilled off by drying under reducedpressure to give 148 mg (0.206 mmol, yield 96.5%) of the title compound.

Melting Point: 206°-209° C. (decomposition)

MS (m/z): 720 (M⁺ +1)

¹ H-NMR(300 MHz,CDCl₃) δ(ppm): 9.43(1H,d,J=7.9 Hz), 7.84 (1H,d,J=8.4Hz), 7.8-7.7(4H,m), 7.5-7.3(11H,m), 7.21(1H,t,J=7.5 Hz), 6.99(1H,dd,J=7.2,5.2 Hz), 4.76 (2H,s), 4.03 (3H,s), 3.37 (1H, dd, J=13.3,7.3 Hz),3.13 (3H,s), 2.23(1H,dd, J=13.1,5.2 Hz), 2.20(3H,s), 1.42 (9H,s)

IR (KBr) v(cm⁻¹): 1736, 1676, 1587, 1458, 1342, 1269, 1143, 1114, 1096,743

EXAMPLE 11

Methyl9α,10β,12α-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylate[Compound (II-1)] ##STR16##

Isopropanol (1000 ml) was added to Compound (VI-1) (50.0 g, 84.0 mmol)obtained in Example 6, and 2N hydrochloric acid (100 ml) was addedthereto at room temperature, followed by stirring for 3 hours whilemaintaining the temperature in a range of 70° to 80° C. After cooling,the mixture was further stirred for 3 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 38.4 g [79.9mmol, yield 95.1%, overall yield from Compound (I) 72%] of the titlecompound.

Melting Point: 252°-257° C. (decomposition)

MS (m/z): 482 (M⁺ +1)

¹ H-NMR(300 MHz,DMSO-d₆) δ(ppm): 9.34 (1H, d,J=7.8 Hz), 8.79 (1H,s),8.16(1H,d,J=7.5 Hz), 8.08(1H, d,J=8.4 Hz), 7.99(1H, d,J=8.4 Hz),7.62(2H,t,J=7.2 Hz), 7.48(1H,t, J=7.6 Hz), 7.42(1H,t,J=7.6 Hz),7.39(1H,m), 5.13(2H, s), 4.10(3H,s), 3.64(1H,dd,J=13.6,7.2 Hz), 3.15(3H,s), 2.30(3H,s), 2.20(1H, dd, J=13.6,5.0 Hz)

IR(KBr) v(cm⁻¹): 1735, 1680, 1460, 1395, 1315, 1272

EXAMPLE 12

Compound (II-1) ##STR17##

Ethanol (3.0 ml) was added to Compound (VI-2) (150 mg, 0.252 mmol)obtained in Example 7, and 2N hydrochloric acid (0.3 ml) was addedthereto at room temperature, followed by stirring for 2.5 hours whilemaintaining the temperature at 30° C. After cooling, the mixture wasfurther stirred for 2 hours under ice-cooling. The precipitated solidwas collected by filtration and the solvent was distilled off by dryingunder reduced pressure to give 115 mg (0.239 mmol, yield 94.9%) of thetitle compound. The compound obtained in this example exhibited the samevalues of NMR, IR, and TLC as the compound obtained in Example 11.

EXAMPLE 13

Compound (II-1) ##STR18##

Ethanol (3.0 ml) was added to Compound (VI-3) (150 mg, 0.203 mmol)obtained in Example 8, and 2N hydrochloric acid (0.3 ml) was addedthereto at room temperature, followed by stirring for 3 hours whilemaintaining the temperature in a range of 70° to 80° C. After cooling,the mixture was further stirred for 2 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 89 mg (0.185mmol, yield 91.2%) of the title compound. The compound obtained in thisexample exhibited the same values of NMR, IR, and TLC as the compoundobtained in Example 11.

EXAMPLE 14

Compound (II-1) ##STR19##

Ethanol (12.0 ml) was added to Compound (VI-4) (150 mg, 0.235 mmol)obtained in Example 9, and 2N hydrochloric acid (0.6 ml) was addedthereto at room temperature, followed by stirring for 3 hours whilemaintaining the temperature in a range of 70° to 80° C. After cooling,the mixture was further stirred for 2 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 90 mg (0.187mmol, yield 79.6%) of the title compound. The compound obtained in thisexample exhibited the same values of NMR, IR, and TLC as the compoundobtained in Example 11.

EXAMPLE 15

Compound (II-1) ##STR20##

Ethanol (3.0 ml) was added to Compound (VI-5) (150 mg, 0.208 mmol)obtained in Example 10, and 2N hydrochloric acid (0.3 ml) was addedthereto at room temperature, followed by stirring for 2.5 hours whilemaintaining the temperature at a range of 70° to 80° C. After cooling,the mixture was further stirred for 2 hours under ice-cooling. Theprecipitated solid was collected by filtration and the solvent wasdistilled off by drying under reduced pressure to give 91 mg (0.189mmol, yield 90.8%) of the title compound. The compound obtained in thisexample exhibited the same values of NMR, IR, and TLC as the compoundobtained in Example 11.

COMPARATIVE EXAMPLE 1

Compound (II-1) ##STR21##

A solution (2 ml) of Compound (I) (184 mg, 0.4 mmol) indimethylformamide was water-cooled and 50% sodium hydride in oil (19.2mg, 0.4 mmol) was added thereto. After 20 minutes, 25 μl (0.4 mmol) ofmethyl iodide was added to the mixture, followed by stirring for onehour. Chloroform (20 ml) was added to the reaction mixture, and thesolution was washed with water and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residuewas purified by silica gel column chromatography (chloroform) to give 65mg (0.14 mmol, yield 34%) of the title compound as a pale yellow powder.

Industrial Applicability

According to the present invention, there can be provided an industrialprocess for selectively and efficiently producing indolocarbazolederivatives which have protein kinase C-inhibiting activity.

We claim:
 1. A process for producing an indolocarbazole derivativerepresented by Formula (II): ##STR22## wherein R⁴ represents loweralkyl, comprising the acidic treatment of a silylated indolocarbazolederivative represented by Formula (VI): ##STR23## wherein R¹, R², and R³independently represent lower alkyl or aryl, and R⁴ has the same meaningas defined above.
 2. A process for producing an indolocarbazolederivative represented by Formula (II) as set forth in claim 1,comprising: silylation of a compound represented by Formula (I):##STR24## for obtaining a compound represented by Formula (V): ##STR25##wherein R¹, R², and R³ have the same meanings as defined above;lower-alkylation of the compound represented by Formula (V) to obtain asilylated indolocarbazole derivative represented by Formula (VI) as setforth in claim 1; and the acidic treatment of the silylatedindolocarbazole derivative.
 3. A silylated indolocarbazole derivativerepresented by Formula (VI) as set forth in claim 1.